Mutations in Kras are associated with ~30% of all cancer patients and ~90% of pancreatic ductal adenocarcinoma (PDAC) patients. The gain of function Kras mutations activate a variety of signaling cascades to drive tumorigenesis. The emergence of animal models that faithfully recapitulate the pathology of the disease and its progression has led to a better understanding of Kras mutation driven tumorigenesis. Genetic and pharmacological manipulation of proteins in these signaling cascades has led to the identification of potential targets for therapeutic intervention. For example, pancreas specific expression of KrasG12D mutant in mice leads to PDAC, however none of the mice developed PDAC when IKK? was concurrently inactivated in the above model. This implicates IKK? as a potential target for therapeutic intervention for Kras mutation driven cancers. Several small molecule IKK? inhibitors were developed by pharmaceutical industry to treat chronic inflammatory diseases. Nearly all IKK? inhibitors developed were ATP-competitive. Despite complete preclinical characterization of many candidates, to date FDA has approved none of them for clinical use. This is because the ATP competitive IKK? inhibitors exhibited on target of site activity associated toxicity in animals. We recently discovered a non-ATP competitive IKK? inhibitor that does not share the toxicity profile observed with ATP competitive IKK? inhibitors. Moreover in an orthotopic pancreatic tumor model, mice treated with our inhibitor showed reduced tumor growth and metastasis compared to vehicle controls. The median survival of mice treated with our inhibitor nearly doubled when compared vehicle treated mice in a mantle cell lymphoma model. Based on these studies in this application we hypothesize that non-ATP competitive IKK? inhibitors are viable therapeutics for Kras mutation driven cancers. Our long-term goal is to develop a lead candidate for IND enabling toxicity studies by optimizing our non-ATP competitive IKK? inhibitor. Towards this goal, in aim 1, we will elucidate the mechanism of action of the non-ATP competitive IKK? inhibitor by conducting biophysical and x-ray crystallography studies with IKK?. In aim 2, we plan to conduct a structure guided hit-to-lead optimization to identify analogs with improved drug- like properties that are suitable for preclinical development. In aim 3, we will evaluate the best inhibitor in combination with the current standard of care in genetic and orthotopic pancreatic cancer models.